Disruption of the AR/ZNF217/PROM2 axis sensitizes prostate cancer to ferroptosis and enzalutamide therapy

Abstract

Abstract Dysregulation of androgen receptor (AR) signaling is a key molecular driver of prostate cancer development and its transition to castration-resistant disease. Although emerging evidence indicates that AR may influence ferroptosis by modulating lipid peroxidation and antioxidant systems, the complete transcriptional network through which AR regulates ferroptosis remains incompletely defined. In this study, we identify the transcription factor ZNF217 as a direct downstream target of AR, which is aberrantly upregulated in prostate cancer and associated with poor clinical outcomes. ZNF217 enhances the transcriptional activity of its downstream effector PROM2, thereby suppressing ferroptosis and promoting cell survival. Functional assays demonstrate that ZNF217 silencing markedly amplifies ferroptotic features, whereas ZNF217 overexpression partially alleviates ferroptosis-induced cellular damage. Building on these findings, we established a drug screening system based on ZNF217 expression and identified the compound RSL3 from a panel of 13 ferroptosis inducers, which potently suppresses ZNF217 expression. Further investigations revealed that combined treatment with RSL3 and the AR antagonist enzalutamide produced a synergistic antitumor response in cellular and animal models, accompanied by marked attenuation of AR/ZNF217/PROM2 pathway activity and reduced tumor burden. Collectively, these findings identify AR/ZNF217/PROM2 signaling as a central determinant of ferroptotic vulnerability in prostate cancer and suggest that targeting this pathway may enhance sensitivity to AR inhibition, providing a molecular rationale for combination therapy in castration-resistant prostate cancer.